Certain 2-iminobarbituric acids



United States Patent 3,428,638 CERTAIN Z-IMINOBARBITURIC ACIDS James M.Dille, Seattle, Wash., and Frank J. Stiefel, Princeton Junction, andMervin Meyer, East Brunswick, N..I., assignors to Carter-Wallace, Inc.,New York, N.Y., a corporation of Maryland No Drawing.Continuation-impart of application Ser. No. 523,922, Feb. 1, 1966. Thisapplication Feb. 10, 1967, Ser. No. 615,057 US. Cl. 260256.4 Claims Int.Cl. C07d 5/22; A61k 27/00 ABSTRACT OF THE DISCLOSURE A group ofcompounds of the formula:

in which R R and R are alkyl having from 2 to 6 carbon atoms, R is alkylhaving from 1 to 6 carbon atoms, and R is hydrogen or alkyl having from1 to 6 carbon atoms. Said compounds are useful for inducing non-hypnoticsedation in warm-blooded animals.

The present invention relates to novel substitutedhexahydropyrimidinediones. More particularly, the invention relates tonovel substituted hexahydropyrimidine-4,6- diones which possess uniquecentral nervous system depressant activities.

The present application is a continuation-in-part of Ser. No. 523,922,filed Feb. 1, 1966 now abandoned, which is in turn acontinuation-in-part of Ser. No. 356,655, filed Apr. 1, 1964, nowabandoned.

The soporific or hypnotic group of central nervous system depressants isa valuable class of medicinal agents widely prescribed by physicians.The general characteristic action of this group ranges from sedation tosurgical anesthesia with increasing dosage. The major use of this classof soporific or hypnotic agents is for the production of sleep. Whenthey are used in lower dose levels as sedatives, this sleep-producingact-ion manifests itself and, therefore, represents a disadvantage tothe use of this class of drugs for pure sedative elfects. Indeed, theyare contraindicated if the patient requires sedation but is expected toundertake normal everyday activities such as driving an automobile orthe like.

It is an object of the present invention to .provide novel substitutedhexahydropyrimidinet,6-diones which possess unique central nervoussystem depressant activities. It is another object of the invention toprovide a novel sedative composition substantially free of thesleep-producing side effects which are common to the presentsoporific-hypnotic group of central nervous system depressants. It is afurther object of the present invention to provide a method of inducingnon-hypnotic sedation in warm-blooded animals. These and other objectsof the invention will become apparent to one skilled in the art in thelight of the instant specification.

In its broad aspect, the invention relates to substitutedhexahydropyrimidine-4,6-diones of the general formula:

Ice

wherein R R and R are alkyl having from 2 to 6 carbon atoms, R is analkyl having from 1 to 6 carbon atoms, and R is selected from the groupconsisting of hydrogen and alkyl having from 1 to 6 carbon atoms. Thealkyl substituents of the compounds of the present invention can bestraight or branched and can be exemplified by ethyl, propyl, isopropyl,n-butyl, l-methylbutyl and the like.

To produce the novel l,5,5-trialkyl 2-alkyliminohexahydropyrimidine-4,6-diones of the invention, the following reactionscheme, wherein R R and R are as hereinbefore defined, R is an alkylradical having from 1 to 6 carbon atoms and X is halogen, is followed:

As indicated above, the appropriate 5,5-dialkyl-2-thiobarbituric acid(I) is converted to the di(-alkali metal) salt (II) by reaction with atleast twice the molar amount of sodium hydroxide in an aqueous medium orof sodium ethylate in an absolute ethanol medium. The resulting disodiumsalt is subsequently reacted with a lower alkyl halide of the formula RX to form the S-alkyl-'l,-5,5- trialkyl-Z-thiobarbimrio acid (III).

After isolation by conventional means, the alkylmercapto intermediate(III) is reacted with the appropriate alkylamine to yield the desired-1,5,5-trialkyl-2-alkylimino hexahydropyrimidine-4,6-dione (IV).

To produce the additional group of compounds contemplated by the presentinvention, i.e., the 1,3,5,5- tetralkyl 2 alkyliminohexahydropyrimidine-4,6-diones, the appropriate 1,5,5 trialkyl 2alkylimino hexahydropyrimidine-4,6-dione (IV) is further converted tothe alkali metal derivative by reaction with a suitable agent, such as,for example, sodium hydride or sodium alcoholate. Preferred results havebeen obtained by using sodium hydride in a dimethylformamide reactionmedium. The resulting sodium salt is then alkylated with a lower alkylhalide of the formula R X, wherein R is the desired alkyl substituentfor the three position.

As hereinbefore indicated, the novel compounds of the present inventionare useful as central nervous system depressants and, in particular, inthe preparation of sedative compositions which are substantially free ofhypnotic effects.

The procedure by which the sedative activity of the compounds ofinvention was evaluated is a modification of the method originallydescribed by Winter in J. Pharmacol. & Exper. Therap., 94, 7 (1948).Such method, widely accepted in pharmacology for the evaluation of thesedative effect of pharmaceutical compounds and commonly referred to asthe hexobarbital potentiation test, measures the ability of the compoundto prolong the duration of sleep induced in mice by the administrationof hexobarbital sodium.

The compound under consideration was administered intraperitoneally tomice in groups of ten at various dosages. Ten minutes after theinjection of the test mate- EXAMPLE A The activities ofl-methyl-2-propylimino-S-ethyl-5-(1-methylbutyl)-hexahydropyrimidine-4,6-dione (Compound 1) and 1 methyl 2propylimino-5 ,5 -diethyl hexahydropyrimidine-4,6-dione (Compound 3)were determined by the hexobarbital potentiation technique. The resultswere as follows:

Dosage Levels (mg/kg.)

Mean Sleeping Compound 1 Compound 3 Hexobarbital Time (min) Sodium TheLD for the above compounds were found to be 488 and 865 mg./kg.,respectively.

EXAMPLE B The sedative activities of 1-propyl-2-propylimino-5- ethyl-(l-methylbutyl)-hexahydropyrimidine-4,6-dione (Compound 4) and1,3-dimethyl-2-propylimino-5-ethyl- 5-( l-methylbutyl)-hexahydropyrimidine-4,6-dione (Compound 5) were determined as above.The following results were obtained:

Dosage Levels (mg/kg.)

Mean Sleeping Compound 4 Compound 5 Hexobarbital Time (min.)

Sodium The LD values for the above compounds were found to be 388'and1072 mg./kg., respectively.

From the above results, it is apparent that the compounds of the presentinvention possess unique sedative activity, as evidenced by theirability to prolong the duration of hexobarbital-induced sleep in mice tohigh degrees. Furthermore, sedation occurs at dose levels at which nohypnotic action manifests itself. In addition, it is apparent that thepresent compounds are non-toxic in amounts required to producesignificant sedation.

The active compounds of the present invention can be administered toWarm-blooded animals in their free form or in the form of theirtherapeutically acceptable salts. The term therapeutically acceptablesalts as used herein and in the appended claims includes organic andinorganic acid addition salts, such as hydrohalides, phosphates,sulfates, acetates, citrates, and the like, as Well as the alkali metalderivatives, such as, for example, the sodium derivative.

In general, while it is possible to administer the active ingredients ofthe present invention as pure compounds, it is preferred to incorporatesaid active ingredients with a suitable pharmaceutical carrier.

The preferred mode of administration is by oral route, with the activeingredient in the form of tablets or capsules. Suitable solidpharmaceutical carriers useful in the preparation of such tablets orcapsules include, for example, starch, lactose, sucrose, glucose,gelatin, and the like.

The active ingredients of the invention in their free form or as theirtherapeutically acceptable salts can also be dissolved in a liquidpharmaceutical carrier, such as, for example, propylene glycol,polyethylene glycol, water, saline, and mixtures thereof, to form asolution suitable for administration by injection or for oraladministration in a palatable form.

Unit dosage forms, such as tablets, capsules or injectable solutions,can contain any suitable predetermined amount of one or more of theactive ingredients, in their free form or in the form of theirtherapeutically acceptable salts, and may be administered as desired.Solid unit dosage forms generally contain from about 25 to about 95% byweight of one or more of the active ingredients. Liquid dosage formsgenerally contain from about 0.1 gram to about grams of activeingredients per 100 ml. of solution. An effective single dose of theactive ingredient is generally in the range of 25 to 1000 mg.

The following examples illustrate the preparation of representativecompounds of the present invention. The physical properties andanalytical value of additional novel compounds which were prepared bysubstantially similar procedures are set forth in Table I which followsherein after.

EXAMPLE 1 Preparation of 1 methyl 2 propylimino 5 ethyl 5- l-methylbutyl-hexahydropyri-midine-4,6-dione (Compound 1) To a solution of 320 g. of50% sodium hydroxide and 484 g.5-ethyl-5-(l-methylbutyl)-2-thiobarbituric acid in 4000 ml. of waterthere was added 624 g. of methyl iodide. The solution was stirred andrefluxed for a period of 4 hours. The mixture was cooled, extracted withether and the ether solution washed with 5% sodium hydroxide and withwater and then dried over anhydrous sodium sulfate.

To the ether solution of S-methyl-l-methyl-S-ethyl-S-(l-methylbutyl)-2-thiobarbituric acid there was added 200 ml. ofn-propylamine and the mixture refluxed for 3 hours. The ether wasremoved and the remaining oil dissolved in 2000 ml. of ethanol,bonecharred and diluted with 5 l. of ice-water. The precipitate whichdeposited was filtered, washed with water and crystallized from 50%aqueous acetone. There was obtained 377 g. of 1 methyl 2 propylimino 5ethyl 5 (1 methylbutyl) hexahydropyrimidine 4,6 dione, M.P. 106 108 C.

EXAMPLE 2 Preparation of 1,3-dimethyl-2-propylirnino-S-ethyl-5-l-methylbutyl) -hexahydropyrimidine-4,6-dione (Compound 5) To a mixtureof 5 g. of 52% sodium hydride in oil in 250 ml. of dimethylformamidethere was added 28.1 g. ofl-methyl-2-propylimino-5-ethyl-5-(1-rnethylbutyl)-hexahydropyrimidine-4,6-dione followed by 15.6 g. of methyl iodide. Theresulting mixture was stirred for 2 hours, then heated to a temperatureof about 80 for a period of one hour.

After standing overnight, the reaction mixture was diluted with 500 ml.of water, the solution extracted with ether and the ether layer washedwith water. The ether solution was extracted with dilute hydrochloricacid, the acid solution alkalized with sodium hydroxide to separate the#free base which was removed with ether, washed, dried, concentrated andthe oily residue purified by distillation. The fraction boiling at -1 10C. at 1011. was collected to yield 17.4 g. of1,3-dimethyl-Z-propylimino- S-ethyl-S (1 methylbutyl)hexahydropyrimidine 4,6- dione. u 1.4980.

TABLE I III 2-imin0 hexahydropyrimidinediones Carbon, percent Hydrogen,Nitrogen, N R, R R R R5 M.P., C. Formula percent percent Oalcd. FoundCalcd. Found Calcd. Found 1 Methyl Propyl H Ethyl l-methylbutyl 106-108CH27Na02- 64. 01 64. 23 9. 67 9. 72 14. 93 14. 94 2 Methyl Isopropyl HEthyl Ethyl 192-194 CnHnNaOa- 60. 30 60. 49 8. 80 8. 87 17 59 17. 34

Methyl Propyl H Ethyl Ethyl 176-178 G12H21N302- 60. 30 60. 53 8. 80 8.84 17. 59 17. 71 4 Propyl Propyl H Ethyl l-rnethylbutyl LiquidC11H3iNsOa 65. 98 66. 15 10. 10 10. 04: 13. 58 13. 61 5 Methyl PropylMethyl Ethyl l-methylbutyl Llqllld CmI-IzvNaOz- 65. 05 64. 84 9. 89 9.76 14. 22 13. 97

Although the invention has been illustrated by the methyl, R is propyl,R is hydrogen, and R and R are preceding examples and table, it is notto be construed ethyl. as being limited thereby. Various departures maybe 0 4. A compound as claimed in claim 1 wherein R and made therefromwithin the scope of the accompanying R are propyl, R is hydrogen, R isethyl and R is 1- claims without departing from the principles of theinmethylbutyl.

vention. 5. A compound as claimed in claim 1 wherein R and What isclaimed is: R are methyl, R is propyl, R is ethyl and R is 1- 1. Acompound of the formula: methylbutyl.

0 R1 R5 l; References Cited \czNm Barre et al. Chemical Abstracts, vol.36 (1942), cols. 4 3853-4. if? Lem-pert-Sreter et al., Berichtc, vol. 93(1960), pp.

0 R3 2290-4. wherein R R and R are alkyl having from 2 to 6 l Berichte,VOL 41 PP- carbon atoms, R is an alkyl having from 1 to 6 carbon atoms,and R is selected from the group consisting of ALEX MAZEL, PrimaryExaminerhydrogen and alkyl having from 1 to 6 carbon atoms. J G ALLAGHERAssistant 2. A compound as claimed in claim 1 wherein R is methyl, R ispropyl, R is hydrogen, R is ethyl and R US. Cl. X.R.

is l-methylbutyl.

3. A compound as claimed in claim 1 wherein R is 260-260, 999.

